Our primary research interest is the analysis of the structure and function of neurotransmitter receptors. Work is currently focused on the nicotinic acetylcholine receptor (AChR). One research area concerns the mechanism of permeability control by the AChR. What portions of the receptor contribute to the ACh binding site or to the structure of the ion channel? How does the binding of ACh change the structure of AChR? What determines whether a drug acts as an agonist (i.e., bind to the ACh site and cause the channel to open) or an antagonist? When drugs block the action of ACh without preventing its binding, where do they bind in the AChR? To answer these questions, protein chemistry and immunological techniques are being used to characterize the structure of the AChR, and biophysical techniques are being used to analyze functional properties of mutant and chemically modified AChRs. A second research area concerns the mechanisms that regulate the distribution of receptors on the cell surface. A striking feature of the vertebrate neuromuscular junction is the fact that AChRs are concentrated at very high density just under the nerve terminal, and that density decreases by orders of magnitude within several microns of the synapse. Four peripheral proteins have been identified on the cytoplasmic surface of the nicotinic postsynaptic membrane. One of these (called rapsyn or 43K protein) is present at a 1:1 ratio with AChR, while the others, including dystrophin, (the gene product deficient in Duchenne's Muscular Dystrophy) and a novel dystrophin-related protein (dystrobrevin or 87K protein), are present at lower abundance. Experiments are underway to determine how these proteins contribute to the stable structure of the postsynaptic membrane.
Selected Publications:
Ramarao, M.K. and Cohen, J.B. (1998) Mechanism of Nicotinic Acetylcholine
Receptor Clustering by Rapsyn. Proc. Natl. Acad. Sci. USA
95: 4007-4012.
Blanton, M.P., Dangott, L.J., Raja, S.K., Lala, A.K. and Cohen, J.B. (1998) Probing the Structure of the Nicotinic Receptor Ion Channel with the Uncharged PhotoactivatableCompound [3H]Diazofluorene. J. Biol. Chem. 273: 8659-8668.
Chiara, D.C., Xie, Y., and Cohen, J.B. (1999) Structure of the Agonist
Binding Sites of the Torpedo Nicotinic Acetylcholine Receptor: Affinity
Labeling and Mutational Analyses Identify gTyr-111/dArg-113 as Antagonist
Affinity Determinants. Biochemistry, in press.